gr8db8, any thoughts on today's call. Oren and I have dissenting view. I'm curious what your thoughts are? I couldn't divine any clues about the GLOBES trial, although I think he hammered home our fear that drop out rates are not significant. david

Oren, I heard the call and disagree. I believe he addressed the imbalance of drop outs here. Also, when referring to the ovarian cancer trials, I believe he was referring to the treatment landscape of PARP inhibitors and how that will change the treatment landscape. In rGBM, he discussed the interim analysis being close to studies' end.

Again, you may be right, but my listen to the conference call doesn't support how the control is doing. He mentioned that when patient's go off study they use checkpoints, and we know that's true as well before patient's going on study, they are using checkpoints.

WTF... yesterday down over a buck, today, jumps at close above 5.50.... Schizophrenic stock move(s).

Not a bad thing to be Thai Lee. It's good to be the king.

A final possibility... could there have been some unforeseen events/deaths/allergic reaction/toxicity which is now being seen? And somebody privy to this data sold of in a hurry. But, I were such a guy with a 100-200K position with said inside info.... I would dribble out of my position over a few weeks because this sale is so blatant that it could easily be tracked back/red flagged in an investigation....

Let's say the trial is stopped in a week. You could easily find out who was selling without any care to the bid / ask on Wednesday PM.

Several possibilities:

1. Someone privy to trial data with whiff of bad news
2. Bad news on planned ovarian trial--FDA doesn't sign off on something
3. Whiff of bad vibes by someone at Oppenheimer
4. A secondary is entering closing stages
5. I just read a theory of a margin call which prompted the seller to tank the stock to obtain capital by 4 pm today. LOL... but it could be true in a sick way.
5. Related to 4. somebody needed cash right away for personal/financial reasons cause their in a bind.

I think it you wanted to exit a substantial position, it would make sense to trade out 25 K shares a day over a few weeks, unless the interim results are due in the AM and that is most likely not going to happen. Any action on the put/call today?

But wouldn't that be a material fact to be disclosed in a formal manner, not just as an aside somewhere? In prior conference calls Dror H stated "drop outs are not an issue" I think is his almost exact quote. I'm glad we will have a conference call in the next few days.

250 K shares or so sold off in the past few minutes. Somebody wanted out in quickly.

The closing seems to have a run for your lives feel to it; secondary or other bad new?

Or maybe something was said that was less than positive at the Oppenheimer conference??

Massive dumping action near close... wonder if a secondary is imminent? Down under 4.8. To be honest I'm kind of glad as I still wish to fund my '17 IRA. LOL.

Me too, but with one caveat. If it works well in rGBM, why wouldn't Roche simply buy it, expanding indications of Avastin with a potential combination approach in different solid tumors. Keep in mind that Avastin is not approved in Europe for rGBM, but VB-111 might alter that reality. Roche might wish to fund several studies combining the two in different solid tumors.

I hope it remains a stand alone company as well, but I think solid rGBM news could lead to a buyout. Just MHO. On the other hand, the company might simply partner with Roche for royalties.

I missed this interesting tidbit from the recent write up.... Very interesting.

https://www.baystreet.ca/articles/research_reports/lifesci/VBLT011917.pdf

"We hosted a key opinion leader (KOL) event at the Society for Immunotherapy of Cancer (SITC) meeting in November 2016 with Dr. Hideho Okada, the director of the Brain Tumor Immunotherapy Center at the University of California San Francisco. At the event, Dr. Okada expressed his view that VB-111 is one of the more exciting treatments in development for GBM."

I think the data in phase II thyroid more than supports a phase III trial, but it's too long of a trial to do right now. I know they have some very good responses with two patients with neuroendocrine tumors from the phase Ia trial who are still on VB-111. So these are two indications.

I think the strategy is to get approval first in rGBM, then expand into RGM, newly diagnosed, ovarian, then with additional funding to basically mirror all indications approved for Avastin. I think it is too heavy a lift for VBLT. A better way to achieve good data on rGBM, then partner with a major pharma/biotech(or buyout).

I see Oppenheimer as well in a few days has just been added on for another "corporate" update.... with no public access.

Roth, now Oppenheimer with late add-on; could they be trying to raise capital? If so, for what? What is the purpose of "corporate updates" other than trying to raise institutional funds; not entirely bad, but just asking is there another explanation?

Key point. For better or worse, Avastin is SOC, the only approved therapy for rGBM... everything else is experimental.

VBLT has data with spider plots showing that high dose VB-111 has attenuated tumor growth compared to low dose VB-111. It stands to reason they a also might have data on rate of tumor growth--in aggregate--for VB-111 plus avastin compared to high dose VB-111 alone although that's not published, but they must have this data from the phase II trial. This data set probably informed them on the phase III trial design.

Yes, Dror has a co-patent on this process... using an adeno viral vector to 'sensitize' endothelial cells in order to make them more radio sensitive.

Oren, I'm especially interested in the radio interview; anything of interest? The radio interview appears most recent, while the videos are longer--kind of a grand rounds in Dror's hospital I assume.

I took a wonderful vacation to Israel when I was 15, but the only Hebrew I seem to remember is "slicha" when I was drunk in Tel Aviv. Wonderful country.

Oren, off topic sort of... are you Israeli? I only ask because if you search vascular biogenies on youtube, you get the standard company stuff, but there are also some fairly lengthy videos regarding Dror Harats lecturing, obviously talking about the companies' technology... from '15 and '16 and, I think, one in '17. I couldn't translate because there is no selection on these you tube videos for the auto-translate feature. I'd be very curious to have a Hebrew speaker on this board translate some of these videos. david

I've read the short thesis on twitter. It never made sense to me. Feurstein hates Dror, but has never described why. He stated the censoring of the patient's in the ovarian trial is a 'red flag', but that isn't true... VBLT did not 'result' the ovarian trial... it was presented by Harvard MD's at ASCO... as to the censoring... the patient's were still alive.

You can made a good short case on VBLT. The trials were small. They were not placebo controlled... also true. This is the rationale short argument and it could very well be true, but the positive results in three different cancers and phase Ia and preclinical all together builds my confidence. Is it possible that a placebo could cause a complete response/remission in rGBM by itself? VB-111 is doing that. The jury is out; i have my eyes wide open, and I think the shorts are wrong.

Exactly right. Don't forget, Avastin is not approved for rGBM in Europe! It is only approved in the US, so, I'm sure some people pay for it, but the price is much higher.... some folks wouldn't be able to get Avastin for the control arm. Avastin is approved for rGBM in Canada, the US, and Israel and in various parts of the world, but not in Europe.

http://www.biopharmadive.com/news/clinical-trial-site-selection-vbl-windtree-drug/437285/

Interesting piece on the CRO selection process. Also, why VB-111 never enrolled in Europe bc the control drug-Avastin was not available for rGBM.

To be honest, I really didn't understand the abstract, I want to see the presentation regarding how it works. There are some additional abstracts at the upcoming April conference looking at leukocyte migration as effected by checkpoint inhibitors. Totally off label, but certain types of lung cancer have like 5-8 year good survival data in 25-30 percent versus 4 percent survival with chemotherapy only. To be sure, this is in the subset of lung cancer patients who have the specific biomarker for checkpoint inhibitors. Still, marveling at the promise of immune therapy against cancer.

http://www.abstractsonline.com/pp8/#!/4292/presentation/3559

If you look at the second interim analysis on the CLDX GBM vaccine trial, I think you'll get a good flavor of VBLT's. The primary CLDX endpoint was futility(they failed)with both groups(vaccine and non-vaccine)having exactly the same events, median overall survival, ect... there was a pre specified efficacy analysis with a p < than .03 which would have been a fairly hard hurdle to crack. I've read in some patent documents on VB111 they planned a similar futility analysis and also a efficacy package in the interim with a p < than .03.

I have various questions I'm not sure about....
1. Assuming they don't pass futility muster, will they obtain any information... KM curves at the time, or at least how many events occurred in both groups, or any other data... amount of partial/complete responses ext.... Dror may have said no, but I'm not sure this is the total case. The party line is only futility, but I think they will learn more IMHO.
2. The way the initial interim analysis was set up, I would have said there is no chance for success with a strict 91 event cutoff since there was no potential time on drug stipulation, now there is... it's not just 108 events, but also that half of the patients will have to have had potential 12 study months on the drug... this makes it more possible to succeed on an interim assuming biological activity of VB-111. I'm assuming about end of July -- early August is when half of the patients were randomized since the pace of enrollment escalated... this pushes the potential interim analysis at around August 1's? of 2017 at the time about half of the patients are enrolled.
3. This leads to the rationale for the change. VBLT petitioned the FDA for the changes not that long ago... it was disclosed in a conference call, but surely planned out many months in advance. So, IMHO it was not based on "what they knew or even surmised" but based on increasing the chances for hitting the hurdle an ending the trial early by achieving success on the interim analysis. Since they strengthen the overall statistical package, they stated this was the reason.... but IMHO, my hunch, is they are hoping/planning the changes based on hitting the interim hurdle.

Take a look at the KM curve separations in the rGBM VB111, the curves separate nicely at around six months and expand a bit thereafter.... same appears to be true for ovarian and thyroid. On the other hand if you look at the rGBM trials, the partial and complete responders did not occur right away, but after several months. Assuming VB-111 works, it will take time... 6-9 months in my opinion to see clear distinction between the groups. Still it's a hard hurdle to pass with ending the trial early by hitting the interim analysis. I would posit about 10 % chance of flunking futility, 30 % change of ending the trial early, and 60 % chance of continuing the trial; before the changes I would have put it at 10 % flunking futility, 85 % at continuing the trial and 5 % of hitting the interim analysis and ending the trial early.

1 more, interesting TVEC plus checkpoint inhibitor potentiating response of an approved viral therapy for melanoma... TVEC....

https://twitter.com/DrNDisis/status/835475521580515329/photo/1

Discuss among yourselves. Rationale for combining VB-111 with checkpoint inhibitors.

Vaccines/viruses are going to see a renaissance - not as monotherapies but in combo w: other inmunotherapies to boost responses #Immunosym

— Sally Church (@MaverickNY) February 25, 2017

Bell: Oncolytic virus turning cold tumor hot. Best when combined with PD1 blockade #immunosym pic.twitter.com/yAOxfFCjiO

— @gulleyj1 (@gulleyj1) February 25, 2017

Right, and if they receive a single Avastin infusion and drop out, they are then included in the survival analysis. If they receive a single VB-111 infusion, they are included in the analysis. The trial had planned to enroll 252 and ended up enrolling 256 patients....so there can't have been too much of a responder overload. Obviously, those who remain in the trial after 5-6 months are by definition responders, but that is true in any trial of rGBM patients by definition considering the median overall survival.

The interesting post-hoc analysis might be comparing patients who received checkpoint inhibitors and VB-111 compared to those who did not.

1. You could not perform this trial, by definition, without it being open label. VB-111 can produce high fever... how can you completely blind any trial with VB-111 for obvious reasons. This is not unusual or atypical for experimental treatments that can produce unexcited toxicity, edema, pyrexia....
2. Another similarity would be the Duke poliovirus rGBM trials or many of the checkpoint trials in their earlier stages.
3. We know from INSPIRE that some of the Avastin only patients dropped out before receiving Avastin. How many? According to Harrats, the CRO told him that drop outs were not a problem or out of line with which is to be expected. I don't think he, legally, can make such a statement if its not true.
4. People with deadly disease drop in and out of trials constantly. They have no choice for obvious reasons. One patients' husband on the INSPIRE forum has ben on like four immune modulating experimental trials for rGBM(including VB-111) over the past 12 months and is reportedly thinking about joining another.
5. It's my understanding the way the trial is calculated is as follows: let's say someone drops out after randomization but before study drug is given... so the computer spits out VB-111/Avastin or Avastin only and, the person is upset, and drops out before Avastin, then he/she would not be calculated, but if a person receives a single dose of Avastin or VB-111 and then drops out due to progression or any other issue, that person's overall survival would still be calculated... so if a person drops out after progression to VB-111 or Avastin, their overall survival data is still inputed into the results, but that would not apply to a person who was randomized into the trial but never got study drug. I actually got this information from an old google patent search on the design of the trial, which interestingly also gave some criteria for early stoppage at the interim with a P < .03.
6. If anything, the trial is already suggested something else interesting: there is no overt interaction between checkpoint inhibitors and VB-111 since many of these patents have received both... not in tandem but within a month or so of one another. There may be some interesting post-hoc analysis of a distinct cohort of patients who receive a checkpoint inhibitor and VB-111.

Yes, '16. If you look carefully at the VB-111 continuous exposure cohort and throw out the folks who succumb to the disease right away and also throw away the complete response, you basically see better control of the tumor than Avastin alone.... i.e., stabilized response for longer periods of time. Another crucial concept that I believe may apply here(and completely unrecognized by the pundits on twitter)is the concept of survival after progression. In certain cancers, an an agent may be dismissed as a failure since progression free survival is not prolonged and patient's progress but they live longer and so the agent increases the so-called survival after progression period. It is a fascinating topic that I may post here with some links later. A final point that is fascinating. If you look at some of the immune therapies against lung cancers in the early trials, it looked like the checkpoint compounds had poorer progression survival than SOC, but they lived longer so overall survival advantage to checkpoint inhibitors. Talk about a group of fascinating paradoxes.

Found another interesting case on Facebook regarding VB-111. Patient had recurrence sometimes around February 2017 with initiation of VB-111 around March/April of VB-111. In this case of one, there has been no growth of the recurrent glioblastoma--stable--after several cycles of VB-111. I hope we see a lot of these.... i.e. longer tumor control with the combination arm. Family is obvious quite content with the 9 months or so of stability.

The most interesting part of today's press release below was the tail of survivors(40%)after many years, but also interesting that 8/17 - 44 % of patients had reduction in tumor size after the first dose in the high dose cohort as opposed to 1/11 - 9% of patients in the low-dose cohort. This sounds like more than placebo to me.

The primary endpoint of the trial, defined as 6-month progression-free-survival (PFS-6) of 25%, was met with a dose response. Forty-seven percent (47%; 8/17) of patients in the therapeutic-dose cohort reached PFS-6, versus 25% (4/12) in the sub-therapeutic cohort, both groups meeting the primary endpoint. Reduction in tumor measurement after the first dose was seen in 44% (7/16) of patients in the therapeutic-dose cohort, compared to 9% (1/11) in the sub-therapeutic-dose cohort. An overall survival benefit was seen with a tail of more than 40% at 3.7 years for the therapeutic-dose cohort (mOS 684 days).

Sorry, I just don't follow your logic on this one. I'm right on my last post, maybe you're right and they botched the phase III trial design; who knows, but I honestly don't think so. As to your argument about limiting Avastin in the phase III trial design; how would that work since it's an FDA approved therapy? Actually the only FDA approved therapy in rGBM.

The more important cohort that closely models the phase III trial design is the continuous cohort, which allows the patent to continue with avastin/VB-111 on progression with VB-111. The more important point I keep returning to is this: is the 15 month overall survival spurious. If so, how is it spurious. That's all that matters to me on the VB-111 story. You've got animal data backing up the hypothesis that VB-111 and also signals of efficacy in three different cancer conditions.

This is the only critique that matters; was the continuous arm cohort flawed, spurious. I saw some on twitter... top biotech names claiming the continuous arm cohort had longer survival/responses because they received more Avastin! Of course they received more Avastin, but Avastin shouldn't alone lead to 15 month overall survival in rGBM.

If your interested, listen again to the PI of the trial, Dr. Chl. discuss these very facts in the KOL presentation from last year. He discusses these very points in more detail on why/what could have caused the 15 month overall survival in the continuous cohort. He explains it better than moi.

The limited disease cohort with VB-111 as mono therapy, then, upon progression, VB-111 was stopped and patients returned to standard of care... nothing, avastin, steroids, who knows and had a median overall survival of a little over eight months, similar to what's expected with Avastin only.

The so-called continuous cohort, began as VB-111 as mono therapy, then, upon progression after FDA amendment, combination therapy with VB-111 with Avastin and had a median overall survival of over 14 months.

The best distillation of this can be found on the archived events on the companies website under the SNO presentation from late '15. There are also waterfall plots with best tumor size responses on this as well.

If you look at the phase II VB-111 cohort, the limited exposure cohort of 22 patients had mono therapy with VB-111 and had an overall survival of between 8-9 months. The continuous exposure cohort received VB-111 mono therapy, then Avastin on exposure with VB-111 so that kind of refutes your thinking. Especially the overall survival in the limited exposure cohort of 8-9 months.

Still, I kind of agree with your SOC arm argument. Why force patients on Avastin? It is used with success to control edema, improve progression free survival, and limit steroid use.... all of which are important uses in rGBM.

But your post doesn't jive with the results of the limited and continuous cohorts in the phase II rGBM trial.

As to the failure of Avastin makes rGBM more lethal. Tumors build resistance to Avastin's mechanism of action with time, leading to failure to Avastin. Considering rGBM, It's pretty lethal to begin with with horrific median survivorship. Optune, vaccines, steroids, Avastin and VB-111.... EVERYTHING fails in time. The goal with VB-111 is to test the thesis that controlling tumor volume for longer periods of time, attenuating tumor growth will increase overall survival. If you can increase overall survival from 8-9 months to over a year, it doesn't sound like much, but it is a very big deal.

Also they will be having an R and D day right after their AACR presentation in early April '16 on the VB600 series.

Oren, you were right. Good talk, but talk based mostly on the January presentation on the web site. No breaking news. I'm kind of surprised Dror did not address this CEO forum.

http://www.abstractsonline.com/pp8/#!/4292/presentation/3559

Not sure, but u could be right.

Not so sure...

I know there will be more color on the VB600 series and oncology implications. The prior PR was very generalized in scope... we may get a plan forward--preclinical--phase I with possible endpoints.

I'm guessing they will/or are applying for a SPA for the ovarian cancer trial. I doubt we will get approval of such a SPA by Monday, but the end of phase II meeting left a lack of details, clearly they are in negotiations about the trial size....120 patients or so and powering of the trial. My guess is they will try to include a SPA.

As to the GLOBE trial, I expect nothing... enrollment complete, waiting interim look so no news most likely on t his point except possible news update on any compassionate access of VB-111.

We may get some color or specifics about the checkpoint inhibitor/VB-111 trial.

The other wildcard is more specifics about the NASH preclinical candidate. Dror mentioned on previous conference calls he will discuss more in first half '17 about plans for out-licensing the lex. platform. This is a fairly good profile conference to lay out such details.

One last point, will this call serve as the quarterly conference call? The last being November '16 isn?